This project will seize on new evidence that excess activity in the CA3 region of the hippocampus occurs both in aged animals with memory impairment and in patients with amnestic Mild Cognitive Impairment (aMCI), a condition that commonly precedes the development of AD. Treatments that target this excess activity in the preclinical animal model are effective in improving memory performance and in rescuing the ability of the targeted neurons to encode new information in memory. Because the CA3 dysfunction studied in animals can now be observed in high resolution functional neuroimaging (fMRI) in patients with aMCI and effective treatments in the preclinical setting have included compounds approved for use in man, here we will test whether a therapeutic intervention based on the animal model can lower excess activation in the CA3 and improve memory in aMCI. High-resolution fMRI will be conducted during a task that places demands on pattern separation, a memory function that specifically depends on the CA3 region. Recent work showed that aMCI patients have impaired memory on the pattern separation task and hyperactive BOLD signals in the CA3/DG during the conditions that tax pattern separation compared to age-matched controls. Significant negative correlations between performance on the target test items and hyperactivity during both encoding and retrieval suggest that excess CA3/DG activation is dysfunctional. The proposed study will experimentally test that hypothesis. The design will determine a treatment regimen that lowers hippocampal hyperactivity in aMCI and assess whether corresponding gains occur in memory performance in the pattern separation task, as predicted by research in the animal model. Participants on placebo and drug, counterbalanced within-subject, will also be tested outside the scanner with other assessments widely used to evaluate memory function. We have assembled an expert team of investigators and an external advisory group to guide this effort in an adaptive design with an exploratory phase (Year 1) and a confirmatory phase (Year 2). Findings from this project would have high impact as an experimental test of whether excess activity serves a compensatory function, as originally suggested in reports of increased hippocampal activation in MCI fMRI, or is in fact a dysfunctional condition, as demonstrated in the animal data. Because increased hippocampal activation in MCI also predicts further decline and progression to AD, the proposed research could be a first step in developing interventions that not only improve cognition in aMCI but also modify progression to AD. That approach is further encouraged by new data on excess neuronal activity in several mouse models of AD and prior research on the production of A beta driven by neural activity, observations that extend a role for excess activity in neurocognitive aging to a possible basis for aging as a primary risk factor for AD. In light of forecasts for a staggering burden of AD in the decades ahead if effective therapies are not found soon, this novel entry point for therapy at an early stage of cognitive impairment has great potential in a critical area of unmet medical need. PUBLIC HEALTH RELEVANCE: Aging is often associated with cognitive deficits, especially decline in memory functions. Aging is also the major risk factor for Alzheimer's Disease (AD), the most common form of dementia. This project will test a new modality of therapy directed at memory impairment in the elderly, which may also have potential to modify a transition from mild cognitive impairment to Alzheimer's disease. It will use tests of memory together with brain imaging to determine the effects of therapy in persons over the age of 55 who meet diagnostic criterion for amnestic mild cognitive impairment. )